This invention relates to ophthalmologically acceptable dopamine antagonists and ophthalmologically acceptable acid addition salts thereof and their use to lower intraocular pressure, especially in the treatment of ocular hypertension and glaucoma.
Glaucoma is an optical neuropathy associated with elevated intraocular pressures which are too high for normal function and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest phase of glaucoma.
Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. Indeed, few advances have been made in the treatment of glaucoma since pilocarpine and timolol were introduced. Timolol, 1-tert-butylamino -3-[(4-morpholino-1,2,5-thiadiazol-3-yl) oxy]-2-propanol, is a, .beta.-adrenergic blocking agent which has been found to be effective in reducing intraocular pressure without many of the undesirable side effects associated with pilocarpine. In addition, timolol possesses advantages over many other .beta.-adrenergic blocking agents, including a lack of local anesthetic action, long duration of activity, and minimal tolerance. Nevertheless, timolol must be used with caution in those patients having elevated intraocular pressure who also suffer from bronchial asthma, sinus bradycardia with greater than first degree block, cardiogenic shock, right ventricular failure secondary to pulmonary hypertension, or congestive heart failure. Further, the concomitant use of timolol with adrenergic augmenting cyclopropane-like drugs must be carefully monitored. These precautions are necessary because even when administered topically to the eye, timolol is sufficiently active that a small portion is absorbed into the systemic circulation where it can affect other systems.
The limitations inherent in the use of timolol are indicative of the need for an alternative form of glaucoma therapy. A very recent approach to improved glaucoma therapy is that disclosed in U.S. patent application Ser. No. 272,889, filed June 18, 1981, entitled "Ophthalmic Compositions and Their Use for Treating Elevated Intraocular Pressure and Glaucoma." Prior to the invention disclosed in the cited application, timolol had been used only in the form of the isomer having the S configuration (L-timolol) or a racemic mixture. The cited application discloses the use of the R stereoisomeric form of timolol (D-timolol) to obtain an intraocular pressure reducing response substantially equivalent to that of the S isomer, but without the undesirable activity in extraocular systems that result from the use of the S isomer.